pt9b00108_si_001.pdf (3.58 MB)
Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors
journal contribution
posted on 2020-03-23, 20:03 authored by Erica
R. Hendrikse, Lydia P. Liew, Rebekah L. Bower, Muriel Bonnet, Muhammad A. Jamaluddin, Nicole Prodan, Keith D. Richards, Christopher S. Walker, Garry Pairaudeau, David M. Smith, Roxana-Maria Rujan, Risha Sudra, Christopher A. Reynolds, Jason M. Booe, Augen A. Pioszak, Jack U. Flanagan, Michael P. Hay, Debbie L. HayClass
B G protein-coupled receptors are highly therapeutically
relevant but challenges remain in identifying suitable small-molecule
drugs. The calcitonin-like receptor (CLR) in particular is linked
to conditions such as migraine, cardiovascular disease, and inflammatory
bowel disease. The CLR cannot act as a cell-surface receptor alone
but rather must couple to one of three receptor activity-modifying
proteins (RAMPs), forming heterodimeric receptors for the peptides
adrenomedullin and calcitonin gene-related peptide. These peptides
have extended binding sites across their receptors. This is one reason
why there are few small-molecule ligands that can modulate these receptors.
Here we describe small molecules that are able to positively modulate
the signaling of the CLR with all three RAMPs but are not active at
the related calcitonin receptor. These compounds were selected from
a β-arrestin recruitment screen, coupled with rounds of medicinal
chemistry to improve their activity. Translational potential is shown
as the compounds can positively modulate cAMP signaling in a vascular
cell line model. Binding experiments do not support an extracellular
domain binding site; however, molecular modeling reveals potential
allosteric binding sites in multiple receptor regions. These are the
first small-molecule positive modulators described for the CLR:RAMP
complexes.
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small-molecule drugsbinding sitesRAMPBinding experimentspeptides adrenomedullinsmall-molecule ligandscalcitonin receptorCalcitonin-like Receptor-Based Receptors Class B G protein-coupled receptorsheterodimeric receptorscell-surface receptorreceptor activity-modifying proteinsβ- arrestin recruitment screenallosteric binding sitesreceptor regionsextracellular domain binding sitecalcitonin-like receptorcell line modelCLRcalcitonin gene-related peptidebowel disease
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